The following references are cited:
F. G. Arsenyan et al., "Influence of Methylcobalamin on the Antineoplastic Activity of Methotrexate," Khimiko-Farmatsevticheskii Zhurnal, vol. 12 (1978), pages 1299-1303 (translation). PA0 P. Boerner et al., "Methionine-sensitive glycolysis in transformed cells," Proc. Natl. Acad. Sci. USA, vol. 82 (1985), pages 6750-5764. PA0 R. Gaggi et al., "The Role of Homocysteine in the Pathogenesis of Arteriosclerosis," Proceedings of the First Congress of the Hungarian Pharmacological Society (Budapest), vol. 2 (1973), pages 287-297. PA0 R. M. Hoffman, "Altered Methionine Metabolism, DNA Methylation and Oncogene Expression in Carcinogenesis," Biochimica et Biophysica Acta, vol. 738 (1984), pages 49-87. PA0 J. C. Linnell et al., "Altered Cobalamin Distribution in Rat Hepatomas and in the Livers of Rats Treated with Diethylnitrosamine," Cancer Research, vol. 37 (1977), pages 2975-2978. PA0 K. S. McCully et al., "Production of Arteriosclerosis by Homocysteinemia," Am. J. Pathology, vol. 61 (1970), pages 1-11. PA0 K. S. McCully et al., "Homocysteine Theory of Arteriosclerosis," Atherosclerosis, vol. 22 (1975), pages 215-227. PA0 K. S. McCully et al., "Homocysteine Thiolactone Metabolism in Malignant Cells," Cancer Research, vol. 36 (1976), pages 3198-3202. PA0 K. S. McCully et al., "Homocysteine Compounds which Influence the Growth of a Malignant Neoplasm," Chemotherapy, S. Karger, Basel, vol. 23 (1977), pages 44-49. PA0 K. S. McCully, "Homocysteine Thiolactone Perchlorate as a Tumor Promotor," U.S. Pat. No. 4,255,443 (1981). PA0 K. S. McCully, "Homocysteine Thiolacatone Salts and Use Thereof as Anti-neoplastic Agents," U.S. Pat. No. 4,383,994 (1983). PA0 K. S. McCully, "N-Homocysteine Thiolactonyl Retinamide and Use Thereof as an Antineoplastic Agent," U.S. Pat. No. 4,618,685 (1986). PA0 K. S. McCully et al., "Antineoplastic Activity of a Rhodium Trichloride Complex of Oxalyl Homocysteine Thiolactone," Cancer Investigation, vol. 5 (1987), pages 25-30. PA0 K. S. McCully et al., "Chemopreventive and antineoplastic activity of N-homocysteine thiolactonyl retinamide," Carcinogenesis, vol. 8 (1987), pages 1559-1562. PA0 K. S. McCully et al., "Homocysteine Thiolactone, N-Homocysteine Thiolactonyl Retinamide, and Platelet Aggregation," Research Communications in Chemical Pathology and Pharmacology, vol. 56 (1987), pages 349-360. PA0 K. S. McCully et al., "Homocysteine Thiolactone in Arteriosclerosis and Cancer," Research Communications in Chemical Pathology and Pharmacology, vol. 59 (1988), pages 107-119.
McCully (1986; McCully et al. 1987, Carcinogenesis) has proposed using N-homocysteine thiolactonyl retinamide, obtained by reaction between trans-retinoic acid and homocysteine thiolactone free base, to reduce pulmonary tumor formation in A/J female mice, treated with tumor-inducing amounts of ethyl carbamate. N-Homocysteine thiolactone retinamide also inhibited the growth of transplanted MUO4 rhabdomyosarcoma in C57BL/6N male mice. N-Homocysteine thiolactone retinamide accordingly has antineoplastic and chemopreventive activity with respect to tumor growth in mice.
N-Maleyl homocysteine thiolactone amide, N-maleamide homocysteine thiolactone hydroperchlorate and rhodium trichloride oxalyl homocysteine thiolactone hydroperchlorate have been proposed as antineoplastic agents (McCully 1983; McCully et al. 1987, Cancer Investigation).
Homocysteine thiolactone perchlorate, however, has been found to promote tumor growth (McCully, 1981). The compound can be used to induce growth of malignant tumors in laboratory animals.
The effects of other homocysteine derivatives on the growth of malignant neoplasms have also been considered (McCully 1976; McCully et al. 1977, 1988).
Homocysteine and related compounds also affect arteriosclerosis (McCully et al. 1970, 1975, 1988; Gaggi et al. 1973). Homocysteine thiolactone and N-homocysteine thiolactonyl retinamide also influence platelet aggregation and may cause thombosis in human and experimentally-induced homocysteinemia (McCully et al. 1987, Research Communications).
Methionine is reported to inhibit glycolysis of Kirsten murine sarcoma virus-transformed rat kidney cells (Boerner et al. 1985).
Other reports correlating abnormal methionine metabolism with carcinogenesis are reviewed by Hoffman (1984).
Increased methylcobalamin concentration in tumors and livers of rats has been reported (Linnell et al. 1977). It has also been proposed that methylcobalamin stimulates growth of transplantable tumors in mice (Arsenayn et al. 1978).
It will therefore be appreciated that the relationship between homocysteine derivatives or cobalamin derivatives and growth of tumors is complex and that the subject is not understood well.
It is an object of this invention to provide a novel compound for inhibiting the growth of tumors. The compound surprisingly includes cobalamin, which is related to recognized tumor stimulants.